The Pediatric Acute Liver Failure Study Group (PALFSG) is the first multi-center, multi-national collaboration to identify, characterize, and develop management strategies for infants, children and adolescents who present with acute liver failure (ALF). Initial funding and support came through the Acute Liver Failure Study Group (NIH 1R01-DK58369-01, William Lee, MD, P.I). This proposal is to establish independent NIH funding to support the current and future activities of this pediatric consortium. PALFSG includes 24 active sites (21 in the U.S., 1 in Canada and 2 in the U.K.) which have collected detailed clinical data from 293 children. We have already redefined ALF in children, demonstrated that the etiologies of ALF in children differs greatly from those seen in adults, described unique features of autoimmune hepatitis associated ALF, and are now conducting a clinical trial using intravenous (IV) N-acetylcysteine (NAC) to treat non- acetaminophen ALF. The Specific Aims of this application are: (1) To collect, maintain, analyze and report clinical, epidemiological, and outcome data in children with ALF, including information derived from serum, tissue, and DNA specimens. Long-term outcome data on patients not enrolled in other NIH-funded pediatric consortia will be collected through the PALFSG. To conserve resources, the NIDDK repositories for tissue, DNA and serum will be utilized. These data will be used to develop predictors of prognosis, analyze trends, and provide materials to investigators. (2) To identify unrecognized mechanisms of hepatocellular injury resulting in ALF in children. Studies will assess the impact of fatty acid oxidation defects, NK cell dysfunction, and acetaminophen on the pathogenesis of ALF. Through these studies, novel treatment strategies may be developed. (3) To continue and complete the double-blind, randomized, placebo controlled trial of NAC to treat non-acetaminophen ALF. The purpose is to examine the safety and efficacy of IV NAC in children with ALF for whom there is no antidote or other specific treatment